PT86292B - A process for the preparation of an antihypertensive pharmaceutical composition comprising a POTASSIUM CHANNEL ACTIVATOR (eg, CROMACALINE) AND AN ACE INHIBITOR (eg, ENALAPRIL) - Google Patents

Abstract

A pharmaceutical product comprising a potassium channel activator antihypertensive agent and an ACE inhibitor antihypertensive agent as a combined preparation for simultaneous, separate or sequential use in therapy of hypertension.

Description

simultaneous, separate or sequential use in hypertension therapy.

The process consists in including said components in said composition, together with a pharmaceutically acceptable support, and mixing them under conditions of non-extreme pressure and temperature.

potassium channel activator is pinacidil or a compound of formula (I)

wherein Y is for example N or CH and R ^, Rg, R ^, Rg, Rg, R? θ Rg are, for example, hydrogen.

An especially preferred compound of formula (I) is chromacalin. The ACE inhibitor is enalapril, lisinopril or captopril.

-30 the present invention relates to

pharmaceutical preparations having antihypertensive activity.

EP-A-173848 describes the use of various benzo-pyran compounds, previously described as antihypertensives, which are potassium channel activators, useful in the treatment of cardiovascular injuries.

EP-A-205292 describes a group of pyran-pyridines, which are also potassium channel activators, useful in the treatment of hypertension, cardiovascular injuries and injuries associated with slight muscle contraction.

United Kingdom Patent No. 1489879 describes the compound N-cyano-N-4-pyridyl-N'-1,2,2-tri-methyl-propyl-guanidine, and in Example 47, a process by which can be prepared. In Drugs of the Future Vol. VI (3), 149,1981, pinacidil is described as a dilating vessel. It is now common knowledge that pinacidil is an activator of the potassium channel.

Enalapril, Lisinopril and

Captopril are inhibitors of the angiotensin-converting enzyme (ACE) with antihypertensive activity, of formulas (A), (B) and (C):

COOH

CH ₂ CH ₂ CHNHCH ((CH ₂ ) ₃ NH ₂ ) CON

COOH

3 '“2?

COOH (B)

(C) and are described in Drugs, 31, (1986); Drugs of the Future, 10 (11), 948 (1985; and Drugs of the Future 6 (11), 731 (1981), respectively.

It has now been found that a combination of a potassium channel activating antihypertensive agent, such as pinacidil or a benzopyran or a pyranopyridine as mentioned above, and an ACE inhibiting antihypertensive agent, such as a compound of formula (A), (B) or (C), or a pharmaceutically acceptable salt thereof of any of the compounds mentioned, has good antihypertensive activity. The efficiency of the combination is greater than can be predicted from a consideration of the antihypertensive activities of the individual components and it appears that a synergistic effect is being produced.

Accordingly, the present invention provides a pharmaceutical product comprising an antihypertensive agent activating the potassium channel, such as pinacidil or a compound of formula (I), or a pharmaceutically acceptable salt thereof:

(I) in qie or Y is N and ® hydrogen; or as Y is C-R ^ where:

either of Rg and Rg is hydrogen and the other is selected from the class consisting of Cg g-carbonyl alkyl, Cg_g-carbonyl alkoxy, Cg_g-carbonyloxy alkyl, Cg_g-hydroxymethyl, nitro, cyano, chlorine, tri-fluoromethyl alkyl, ^C1 6 alkylsulfinyl ^{-su f} l> Cg_g alkyl-sulfonyl, sulfinyl, alkoxy Cg_g, g alkoxy-Cg alkylsulfonyl, Cg_g-carbonylamino, lower alkoxy carbonylamino g-Cg, Cg alkyl-thiocarbonyl g, Cg_g alkoxy-thiocarbonyl, alkyl Cg_g-thiocarbonyloxy; ^1-mercapto-C 2-7 alqilo 'formyl or amino-sulfinyl, aminosulfonyl or aminocarbonyl it with the amino moiety optionally substituted by one or two alkyl groups Cg_g or alkyl Cg_g-sulfinylamino, C ₁ _g alkyl-sulfonylamino , Cg_g-sulfinylamino alkoxy or Cg_g-sulfonylamino alkoxy, or ethylenyl terminally substituted by Cg alkyl g-carbonyl, nitro or or —C (Cg alkyl θ) ΝΝΗ ₂ ; or one of Rg and Rg is nitro, cyan or is methoxy or amino optionally cyano, or -C (Cg_g alkyl) -NOH alkyl Cg_g-carbonyl and the other substituted by one or two Cg_g alkyls or by Cg alkanoyl one of Rg and is hydrogen or alkyl and the other is ^C i_4 alkyl * ^{10 or} both Rg and R ^ are poly-methylene ^C2-5 '

R ₅ is hydrogen, hydroxy, Cg_g alkoxy or Cg_g acyloxy; θ

Ρθ is hydrogen; or

Rg and Rg taken together form a bond;

R? is hydrogen, C _g alkyl optionally substituted by hydroxy, g, g alkoxy-carbonyl or carboxy, _C1 _g alkyl substituted by halogen. or ^C 2-6 alkenyl ^'0 yl ^air or heteroaryl optionally substituted by one or more groups or atoms selected from the class consisting of alkoxy hydroxy, halogen, trifluoromethyl, nitro, cyano, carboxylic acyl , ^or amino or aminocarbonyl optionally substituted by one or two C 1-4 alkyl groups; and

Rg is hydrogen or alkyl g; or

R? and R _g taken together form polygene Cg_ ₄ or -CH _O - (CH _O ) -Z- (CH _n ) where men are integers from 0 to 2, such that m + n is 1 or 2 and Z is oxygen, sulfur or NR, wherein R is hydrogen, C1 _g alkanoyl, C ₃ · ?, phenyl- naphthylcarbonyl, phenylcarbonyl or benzilaarbonilo optionally substituted in the phenyl or naphthyl ring by one or two alkyls C? _g, C ^ _ alkoxy or halogen; mono- or bi-cyclic hetero-arylcarbonyl;

X is oxygen or sulfur; and the RgNCXR ^ portion is trans relative to the Rg group, when

Rg is hydroxy, C1-4 alkoxy or acyloxy and an inhibiting antihypertensive agent, such as a compound of formula (A), (B) or (C):

- ^CH 2 ^CH 2 ^< [ ^{HNHCH (CH} 3> ^C0N

COOC RI ^{2 5} COOH (A)

ÇHNHCH ((CH ₂ ) ₃ NH ₂ )

COOH

COOH (B)

(C) in the form of a combined preparation for simultaneous, separate or sequential use in hypertension therapy.

In a preferred aspect, the active components of the product are administered simultaneously.

the present invention further provides a pharmaceutical composition, which comprises an antihypertensive agent activating the potassium channel, such as pinacidil or a compound of formula (I), or a pharmaceutically acceptable salt thereof and an ACE inhibiting antihypertensive agent, as a compound of formula (A), (B) or (C), in combination with a pharmaceutically acceptable support.

The invention further provides the use of a potassium channel activating antihypertensive agent, such as pinacidil or a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an ACE inhibitor antihypertensive agent, as a compound of formula (A), (B) or (C), in the manufacture of a pharmaceutical preparation for simultaneous, separate or sequential use in antihypertensive therapy.

Preferred and suitable values for the various groups or atoms in formula (I) are those described for the corresponding variables in EP-A-76075, 91748, 93535, 95316, 120426, 126311, 126380, 126367, 138134 and 205292. of the corresponding North American Patents are US Patent Nos. 4446113, 4542149, 4510152, 4481214, 4496565, 4555509, 4610992, 4571406, 4629734, 4575511, 4677116 and U.S. Serial No. 871711, respectively.

A particularly preferred compound of formula (I) is the compound of Example 1 of EP-A-76075 and United States Patent No. 4446113, (I) -6-cyano-3,4-dihydro-2,2- dimethyl-trans-4- (2-oxo-1-pyrrolidinyl) -2H-benzo-b7-pyran-3-ol.

Examples of pharmaceutically acceptable salts are described in the aforementioned European Patent references, in which the subject matter is incorporated herein by reference.

The compositions and products described above have an activity that lowers blood pressure, and are potentially useful in the treatment of hypertension.

The compounds of formula (I), and their salts can be prepared as described in the above mentioned references of European and North American Patents.

pinacidil and its salts can be prepared as described in the U.K. Patent mentioned above.

product of the invention can be administered orally to humans and can be composed in the form of syrup, tablets, or capsules for separate, sequential or simultaneous administration.

However, they can be adapted for other modes of administration, for example parenteral administration for patients suffering from heart failure. Other alternative modes of administration include transdermal or sublingual administration.

Generally, compositions containing from about 0.5 to 25 mg of a compound of formula (A), (B) or (C) per mg of pinacidil or a compound of formula (I) or a pharmaceutically acceptable salt thereof, are effective, depending on the activity of the potassium channel activator.

In order to obtain consistency in administration, it is preferred that the composition of the invention is in the form of a unit dose. Suitable unit dosage forms include tablets, capsules and powders in bags or bottles. These unit dosage forms may contain a total of from 0.5 to 100 mg of active compounds of the invention and more usually from 0.5 to 50 mg, for example 0.5 to 25 mg, such as 0.5; 1.2; 3, 5, 10; 15 or 20 mg. These compositions can be administered from 1 to 6 times a day, more usually from 2 to 4 times a day in such a way that the daily dose is from 0.5 to 200 mg for a 70 kg human adult and more particularly from 0.5 to 25 mg with the above indicated dosage range, no adverse toxicological effects are indicated with the compounds of the invention.

The compositions of the invention can be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder,

a lubricant, a management agent. They are formulated in a conventional manner, for example in a manner identical to that used for antihypertensive agents.

It is highly preferred that the potassium channel activating antihypertensive agent, such as pinacidil or the compound of formula (I) or a pharmaceutically acceptable salt thereof and the ACE inhibiting antihypertensive agent, such as the compounds of formula (A) , (B) or (C) are administered in the form of a unit dose composition, such as an oral unit dose or parenteral composition.

These compositions are prepared by mixing and are suitably adapted for oral or parenteral administration, and as such may take the form of tablets, capsules, liquid oral preparations, powders, granules, expectorant tablets, reconstitutable powders, injectable and infusion solutions or suspensions or suppositories . Orally administrable compositions are preferred, in particular oral shaped compositions, as they are the most convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, pressure agents, lubricants, disintegrants, colorants, taste agents and humidifiers. be coated according to methods well known in the art.

Suitable fillers to be used include cellulose, mannitol, lactose and other similar agents. Suitable disintegrating agents include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

These solid oral compositions can be prepared by conventional methods of agglutination, filling or compression.

Repeated mixing operations can be used to deliver the active agent through those compositions that employ large amounts of fillers. Naturally, these operations are conventional in this field.

Liquid oral preparations can be in the form of, for example, oily or aqueous suspensions, solutions, emulsions, syrups, or elixirs, or they can be presented as a dry product, to be reconstituted with water or another suitable vehicle, before use. These liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fatty agents, emulsifying agents , for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, such as glycerin esters, propylene glycol, or ethyl ether; preservatives, for example methyl or ethyl p-hydroxybenzoate or sorbic acid, and if desired, taste or color agents.

Oral formulations also include delayed release formulations, such as tablets or granules with an enteric coating.

For parenteral administration, fluid unit dosage forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are usually prepared by dissolving the compound in a vehicle and sterilizing by filtration prior to filling into vials or

suitable and sealed ampoules. Advantageously, adjuvants such as a local anesthetic, preservatives and buffering agents are also dissolved in the vehicle. To increase stability, the composition can be frozen after filling into the bottles and the water is removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in a vehicle instead of being dissolved and is sterilized by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or a wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.

In addition, these compositions may contain more active agents like other classes of antihypertensive agents and diuretics.

It is common practice that the compositions are usually accompanied by written or printed instructions for the use of the medical treatment to which it relates.

It is to be appreciated that each component of the product of the invention can be administered in different ways.

The present invention further provides a method of treating hypertension in mammals including man, which comprises administering to the animal suffering an antihypertensive effective amount of a pharmaceutical composition comprising an antihypertensive agent activating the potassium channel, such as pinacidil or a compound of formula (I) or a pharmaceutically acceptable salt thereof and an ACE-inhibiting antihypertensive agent, such as a compound of formula (A), (B) or (C), in combination with a pharmaceutically acceptable support.

The following pharmacological data illustrate the invention.

Ο compound 1 is ο 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4- (2-oxo-1-pyrrolidinyl) -2H-benzo / b7 pyran-3-ol (o compound of Example 1 of EP-A 76075 and US Patent No.4446115);

Compound 2 is trans-3,4-dihydro-2,2-di-methyl-4- (2-oxopyrrolidin-1-yl) -2H-pyran / ^- 3, 2-c7 pyridin-3- ol (the compound of Example 1 of EP-A-205292);

Compound 3 is 6'cyano-3,4-dihydro-2,2-di-methyl-trans-4- (N-3-methyltetrahydro-2-pyrimidone) -2H-benzo / ~ b7pyran-3- ol (the compound of Example 12 of EP-A-107423 and US Patent No.4496565);

Compound 4 is trans -4-N-acetyl amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo / ^- b7piran-3LO (Compound of Example 2 of EP- A-95316 and US Patent No.4448214).

Pharmaceutical Data

The potency of the antihypertensive response of the compounds of formula (I) has been observed in male, conscious, spontaneously hypertensive (SHR) rats, when the compounds are combined with the angiotensin conservative enzyme inhibitor (I), enalapril .

For experimentation purposes, 36 rats were randomly divided into 4 groups, each of 9 rats. Systolic blood pressure (SBP) was measured non-invasively, using an inflammation-pricking tail technique described in the above-mentioned European Patent references. The record of the experiment was as follows.

TIME GROUP 1 GROUP 2 GROUP 3 GROUP 4 (H) 0 vehicle Enalapril vehicle Enalapril (Water) 3 mg / kg po 5 ml / kg po 3 mg / kg 5 ml / kg po POWDER 0.75 vehicle vehicle compound 1 compound 1 (Water) 5 ml / kg po 0.3 mg / kg 0.3 mg / kg POWDER POWDER

SBP was measured in each rat before the treatments described above and then again at 1.75; 2.75 and 4.75 pm. The results are shown in Table I.

-15The zrd

O (d • H β

PAINTING

CD.

O

the irtí

O (0 • H

S-i (0 co

O

CU □

O!

O (d H íh

Π5> dP

CM

The ass D K O

m & «Çj * X- * «Tf The 5 C co JL fH in G co co Ç 1 ι - 1 1

co +1 r *

CN CM CO CM -H 44 •H 44 co rM in CM 1 T CM 1 r-H 1

CM CM CM -H +1 +1 r- 44 rM in r ·! t 00 1 r4 1 rH 1

0 i (d U rd CM fn ra CM CM 44 rd ^U1 44 . 44 O > 44 Φ Γ- | r-4 1 rH dP - ' 1 1 1

H o

lD in LH m Γ * Ç- r * t K. • w. · « O O r-4 CM

Eh

The results for compounds 2 to 4 were as follows:

COMPOUND 2 (A) COMPOUNDS

COMPOUND

COMPOUND

CONTROL

TIME

0 24616 0 _z 6 mg / kg 24416 POWDER 3 mg / kg po 24713 2 + (A) 24614 0.75 -3 ± 2 112 -9H -8 ± 1 1.75 -4 ± 2 -20 ± 2 -2212 -4515 2.75 -2 ± 3 -1213 -1413 -3214 4.75 -8 ± 2 -1112 -16 ± 2 -3113 COMPOSITE .. 3 TIME CONTROL COMPOUND 2 _; 0 mg / kg 3 Ρθ COMPOUND 3 mg / kg (A) PO COMPOUNDS 3 + (A) 0 251 ± 5 25316 25414 255 ± 3 0.75 0 ± 2 0 ± 3 -812 -13 ± 2 1.75 0 ± 2 -2013 -1013 -44 ± 5 2.75 212 -2213 -1214 -48 ± 4 4.75 -6 ± 3 -21 ± 3 -21 ± 3 -4813 COMPOUND 4 TIME CONTROL COMPOUND 4 0 ^ 15 mg / kg po COMPOUND 3 mg / kg ' (A) POWDER COMPOUNDS 4 + (A) 0 27514 28115 28015 28511 0.75 -2 ± 1 012 -4 ± 2 -6 ± 2 1.75 -6 + 2 -2614 -912 -4214 (7) 2.75 -6 ± 1 -2314 -12 ± 3 -4112 4 _; 75 -2 ± 1 -13 ± 2 -1412 -3212

The record of experimentation for pina cidil was as follows:

TIME GROUP 1 GROUP 2 GROUP 3 GROUP 4 (H) 0 vehicle Enalapril vehicle Enalapril 5 ml / kg po 3 mg / kg po 5 ml / kg po 3 mg / kg po 0.75 vehicle vehicle Pinacidil Pinacidil 5 ml / kg po 1 mg / kg po 1 mg / kg po

SBP was measured in each rat before the treatments described above and then again at 1.75; ; 2.75 and at 4.75 h. The results are shown in Table II.

Claims (7)

CLAIMS there. - Process for the preparation of a pharmaceutical composition, characterized in that said composition includes a potassium channel activating antihypertensive agent and an ACE inhibiting antihypertensive agent (enzyme, angiotensin converting agent), and a pharmaceutically acceptable support, and for understanding the mixture of the active ingredients and the support under non-extreme conditions of pressure and temperature, preferably at room temperature and atmospheric pressure. 2 ^a . Process according to claim 1, characterized in that the potassium csial activating antihypertensive agent is pinacidil or a compound of formula (I), or a pharmaceutically acceptable salt thereof: where either Y is N and R ₂ is hydrogen; or Y is CR ^, where: any of R ^ and R ₂ is hydrogen and the other is selected from the class consisting of alkyl g-carbonyl, alkoxy, g-carbonyl, alkyl g-carbonyloxy, alkyl g- hydroxymethyl, nitro, cyano, chlorine, trifluoromethyl, alkyl C ₁ _g-sulfinyl, C ₁ _g-sulfonyl, alkoxy g-sulfinyl, Cg_g-sulfonyl alkoxy, C 4 _g-carbonylamino, C 4 _g-carbonylamino alkoxy, C 4 _g-thiocarbonyl, alkoxy g-thiocarbonyl, alkyl C 2 _g-thiocarbonyloxy, 1-mercapto- ^C 2 ~ y 'alkyl formyl, or amino-sulfinyl, amino-sulfonyl or amino- carbonyl with the amino moiety optionally substituted by one or two alkyl groups C ^ _ _g _ alkyl or C ^ _g -sulfinilamino, C ^ _ _g alkyl sulfonylamino, C ^ _ alkoxy or alkoxy -sulfinilamino _{g, r} - sulfonylamino, or ethylenyl terminally substituted by C ₁ _ _g -carbonyl, nitro or cyano alkyl, or -C (alkyl _g ) NOH, or -C (alkyl ^c ^ _g ^ ^NH 2 * or one of R ^ and R £ is nitro, cyano, or g-carbonyl alkyl and the other is methoxy or amino optionally substituted by one or two _g alkyls or by alkanoyl γ; one of R ^ and R ^ is hydrogen, or alkyl θ the other is alkyl or both Rg and R ^ are poly-methylene ^R5 ® hydrogen, hydroxy, C ^ _ _g or ^acyloxy 2_7Í ^{and Rg} θ hydrogen; or R _g and R _g together form a bond; R ^ are hydrogen, C ^ _ _g optionally substituted by hydroxy, alkoxy _g , alkoxy _g -carbonyl or carboxy, alkyl _g substituted by halogen, or alkenyl C1 _g ; aryl or heteroaryl optionally substituted by one or more groups or atoms selected from the class consisting of alkoxy C ^ _ _g, hydroxy, halogenated NIO, trifluoromethyl, nitro, cyano, acyl, carboxylic acid C ^ _ ^ g; or amino or amino-carbonyl optionally substituted by one or two alkyl groups; and Rg is hydrogen or C ₁ _ _g alkyl; or ^{and R} g taken together form polymethylene Cg_ ^ or -Cl ^ -ClI ^) -Z-ÍCt ^^ -, where men are integers from 0 to 2, such that m + n is 1 or 2 and Z is oxygen, sulfur or NRg, where Rg is hydrogen, C4-alkyl, alkanoyl ^ 2-7 'enyl-naphthyl-carbonyl, phenyl-carbonyl or benzyl-carbonyl optionally substituted on the phenyl or on the naphthyl ring by one or two _g Cj_ alkyl, alkoxy ^ _ _g, ° ^u halogen; heteroaryl carbonyl mono- or bi-cyclic; X is oxygen or sulfur; and the RgNCXR? is trans relative to the R _g group, when R _g is hydroxy, alkoxy _g or acyloxy?; and the ACE-inhibiting antihypertensive agent, is a compound of formula (A), (B) or (C): ί · CH ₂ CH ₂ CHNHCH (CH ₃ ) CON cooc ₂ h ₅ COOH (A) α ^^ CH-CH CHNHCH ((CH ^{2 2} I COOH COOH (B) 3rd. - Process according to claim 2, characterized in that the activator antihypertensive agent potassium channel present formula (I) wherein Y is N or CR ^, where is nitro, cyano, alkyl or C ^ _ ₃ -carbonyl, and R ₂ is hydrogen. 4th. Process according to claim 2 or 3, characterized in that R ₃ and R 4 are both methyl groups. 5th. Process according to any one of claims 2, 3 or 4, characterized in that R ^ and Ρθ, taken together to form polymethylene ^C 3_4 ^{or -CH} 2 ^- ( ^CH 2 ^ n ^-Z_ ^ ^Cf ^ 2 ^ m "' ⁱⁿ ^ ^{u m 'n' EZS} ^ ° ^as defined in claim 2; or R is hydrogen or methyl and is ethyl, methyl, hydrogen or phenyl optionally substituted with one, two, three or four groups or atoms selected from methyl , methoxy, hydroxy, fluoro ei * -22chlorine. 6 ^. Process according to claim 5, characterized in that the compound of formula (I) is (+) - 6-cyano-3,4-dihydro-2,2-di-methyl-trans-4- (2- oxo-1-pyrrolidinyl) -2H-benzo / b7-pyran-3-ol. 7th. Process according to claim 2, characterized in that a composition is prepared containing 0.5 to 25 mg of a compound of formula (A), (B) or (C) per mg of pinacidil or a compound of formula ( I), or a pharmaceutically acceptable salt thereof. 85. - Method of treatment of hypertension in mammals, characterized in that the administration to mammals of an effective, non-toxic amount of a combination of an antihypertensive agent that activates the potassium channel and an antihypertensive agent that inhibits ACE , the daily dosage range being from 0.5 to 200 mg for a 70 kg human adult and more particularly from 0.5 to 25 mg.